Inhibition of the hepatic cytochrome P-450-dependent monooxygenase system by rubratoxin B in male mice

Abstract

The in vivo effects of rubratoxin B on hepatic mixed-function oxidase enzymes in male mice were examined. Animals were exposed to a single ip dose of 0.25, 0.5, 1.0, or 1.5 mg rubratoxin B/kg or daily doses of 0.5 mg/kg rubratoxin B for 14 days. Rubratoxin B (1 mg/kg) markedly inhibited the hepatic cytochrome P-450-dependent monooxygenase system when measured 1, 16, 48, 72, and 96 hr after a single exposure. At 48 hr, dose levels as low as 0.25 mg rubratoxin B/kg inhibited pentobarbital hydroxylase and ethylmorphine demethylase. These same enzymes, along with cytochrome P-450 content and NADPH-dependent dehydrogenase, continued to be depressed to about the same degree when animals were exposed to rubratoxin B for 14 days. NADPH-cytochrome c reductase was not affected by rubratoxin B on single or multiple exposure. These studies demonstrated that a single exposure to rubratoxin B caused a depression in activity of the cytochrome P-450 dependent monooxygenase enzyme system and that after maximum inhibition by a single dose at 48 hr, the trend was for the enzymes to return to control values.